Mitochondrial control of apoptosis: an overview

1999 ◽  
Vol 66 ◽  
pp. 1-15 ◽  
Author(s):  
Guido Kroemer
Keyword(s):  
Transmembrane Potential ◽  
Mitochondrial Permeability Transition ◽  
Ion Selectivity ◽  
Permeability Transition ◽  
Critical Event ◽  
Intact Cells ◽  
Isolated Mitochondria ◽  
Pore Opening ◽  
Mitochondrial Megachannel

The mitochondrial permeability transition (PT) pore, also called the mitochondrial megachannel, is a multiprotein complex formed at the contact site between the mitochondrial inner and outer membranes, exactly the same location at which Bax, Bcl-2 and Bcl-XL are particularly abundant. The PT pore participates in the regulation of matrix Ca2+, pH, transmembrane potential and volume, and functions as a Ca2+-, voltage-, pH- and redox-gated channel with several levels of conductance and little, if any, ion selectivity. We have obtained three independent lines of evidence implicating the mitochondrial PT pore in apoptosis. First, in intact cells, apoptosis is accompanied by an early dissipation of the mitochondrial transmembrane potential, ΔΨm. In several models of apoptosis, specific agents inhibiting the mitochondrial PT pore abolish this dissipation of the ΔΨm and simultaneously prevent activation of downstream caspases and endonucleases, indicating that PT pore opening can be a critical event of the apoptotic process. Secondly, mitochondria are rate-limiting for caspase and nuclease activation in several cell-free systems of apoptosis. Isolated mitochondria release apoptogenic factors capable of activating pro-caspases or endonucleases upon opening of the mitochondrial megachannel in vitro. Thirdly, opening of the purified PT pore complex reconstituted into liposomes is inhibited by recombinant Bcl-2 or Bcl-XL, two apoptosis-inhibitory proteins that also prevent PT pore opening in cells and isolated mitochondria. Altogether, our results suggest that PT pore opening is sufficient and (mostly) necessary for triggering apoptosis. The implications of these findings are examined in the light of pharmacological interventions in apoptosis.

scholarly journals Phytochemicals and in vitro anti-apoptotic properties of ethanol and hot water extracts of Cassava peel of Cassava (Manihot Esculenta Crantz) biogas slurry following anaerobic degradation

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Olaniyan Oluwaseyi Paul ◽  
Ajayi Ebenezer O. Idowu
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Biogas Production ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Hot Water ◽  
Crude Extracts ◽  
Permeability Transition Pore Opening ◽  
Pore Opening ◽  
Cassava Peel

Abstract Background Wastes emanating from cassava (Manihot Esculenta Crantz) processing in African countries significantly contribute to environmental pollution, besides, such toxic wastes contribute to greenhouse gas emission. Although cassava peel has been successfully used as a raw material in mushroom cultivation, feedstock for livestock, biogas production but the bio-transformed products recovered from the anaerobic digestion of cassava wastes, especially the peels have often been overlooked. Therefore, this research aimed at quantifying the secondary metabolites in the slurry recovered from ethanol and hot water extraction of cassava peel subjected to biogas production, in vitro, for anti-apoptotic properties. Methods Fresh cassava peels were allowed to ferment anaerobically to produce three states of matter; gas, solid, and liquid/slurry. The slurry was extracted using 95 % ethanol and 100 oC hot water to obtain crude extracts, which were then subjected to anti-apoptotic screening using the mitochondrial swelling assay. The qualitative phytochemical analysis of the crude extracts was done using standard methods. Further characterization of the crude extracts was done by FTIR for the chemical elucidation of the functional groups present. Results The qualitative phytoconstituents revealed that the slurry extracts are naturally enriched with alkaloids, steroids, flavonoids, and saponins. The infrared spectrum of the crude extracts revealed the presence of hydroxyl, alkane, carboxyl groups in the ethanol extract, and hydroxyl, alkene, amide, carbonyl groups in the hot water extract. In the presence and absence of exogenous Ca2+, both extracts of the slurry induced liver mitochondrial permeability transition pore opening albeit at low amplitude swelling as the mean absorbance was less than one (at 540 nm). Conclusions Based on these results obtained, the crude extracts of cassava peel biogas slurry have been proven to possess bioactive compounds that could induce liver mitochondrial permeability transition pore opening, in vitro.

Ca2+ depletion prevents anoxic death of hepatocytes by inhibiting mitochondrial permeability transition

1995 ◽  
Vol 268 (3) ◽  
pp. C676-C685 ◽  
Author(s):  
J. G. Pastorino ◽  
J. W. Snyder ◽  
J. B. Hoek ◽  
J. L. Farber
Keyword(s):  
Culture Medium ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Rat Hepatocytes ◽  
Acetoxymethyl Ester ◽  
Intact Cells ◽  
Mitochondrial Permeability ◽  
Isolated Mitochondria ◽  
The Matrix ◽  
Matrix Concentration

Removal of Ca2+ from the culture medium or treatment with the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N', N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM) prevented the killing of rat hepatocytes by anoxia and rotenone, but not by cyanide. Neither manipulation prevented the loss of the mitochondrial membrane potential or the depletion of ATP. A mitochondrial permeability transition (MPT) was demonstrated in digitonin-permeabilized hepatocytes as an increased [3H]sucrose-accessible space sensitive to cyclosporin A (CyA). Ca2+ depletion by either means prevented the MPT measured in intact cells made anoxic or treated with rotenone. In isolated mitochondria deenergized by rotenone, BAPTA-AM prevented the MPT induced by palmitoyl CoA. By contrast, in isolated mitochondria deenergized by cyanide, BAPTA-AM alone did not prevent the MPT. Rather, BAPTA-AM plus CyA were required. Similarly, the killing of cultured hepatocytes by cyanide was prevented by BAPTA-AM plus CyA, but not by either agent alone. The MPT in intact cells treated with cyanide was also prevented by BAPTA-AM plus CyA. These data define a specific requirement for Ca2+ in the killing of hepatocytes that follows the inhibition of electron transport. A model is presented in which the MPT depends on factors that modulate the sensitivity of the permeability transition to the matrix concentration of Ca2+.

scholarly journals Selenite sensitizes mitochondrial permeability transition pore opening in vitro and in vivo: a possible mechanism for chemo-protection

2003 ◽  
Vol 370 (1) ◽  
pp. 283-290 ◽  
Author(s):  
Shani SHILO ◽  
Anna ARONIS ◽  
Rita KOMARNITSKY ◽  
Oren TIROSH
Keyword(s):  
Complex I ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Mitochondrial Swelling ◽  
Rat Liver Mitochondria ◽  
Mitochondrial Permeability ◽  
Cellular Apoptosis ◽  
Pore Opening

There is a known connection between selenium supplementation and chemo-protective anti-cancer activity. This biological phenomenon may be due to the ability of selenium to instigate cellular apoptosis. However, the mechanism by which selenium promotes cellular apoptosis is still obscure. The present study shows that sodium selenite, a common dietary form of selenium, promotes the mitochondrial permeability transition (MPT) in isolated rat liver mitochondria both in vitro and following in vivo supplementation. A low selenium concentration (0.1—10μM) strongly induced cyclosporin A-sensitive mitochondrial swelling. Selenium also promoted both calcium release from the matrix of isolated mitochondria and uncoupled respiration. The MPT-inducing effect of selenium provoked the release of cytochrome c, a pro-apoptotic factor, into the incubation medium. Selenium did not increase intra-mitochondrial peroxide production, but did consume endogenous mitochondrial glutathione. Moreover, the effect of MPT induction was greatly potentiated in the presence of thiol-bearing antioxidants, e.g. N-acetylcysteine and lipoamide. During MPT progression, selenium induced NADH oxidation via electron acceptance from complex I. Supplementation for 20 days with 16p.p.m. selenium in the drinking water of rats increased the propensity of mitochondria to undergo the MPT. More marked mitochondrial swelling in response to calcium and lower calcium-uptake capacity were observed, in the absence of liver damage or the intensive oxidation of reduced glutathione. Therefore selenite facilitates MPT pore opening via its thiol- and NADH/complex I-dependent reduction, and thereby may provide chemo-protection by potentiation of the capacity of the mitochondria to regulate programmed cell death. Data from the present study suggest that selenium can regulate important mitochondrial functions both in vivo and in vitro.

scholarly journals Long Lasting Reversibility of the Mitochondrial Permeability Transition in Saccharomyces cerevisiae

2021 ◽  
Author(s):  
Lilia Morales-García ◽  
Carolina Ricardez -García ◽  
Paulina Castañeda-Tamez ◽  
Natalia Chiquete-Félix ◽  
Salvador Uribe-Carvajal
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Transmembrane Potential ◽  
Mitochondrial Permeability Transition ◽  
Energy Charge ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Isolated Mitochondria ◽  
Opening And Closing ◽  
Open Position

Abstract: The Saccharomyces cerevisiae mitochondrial unspecific pore (ScMUC) is an uncoupling unspecific pore that shares some similarities with the mammalian permeability transition pore (mPTP). When open, both channels deplete ion and proton gradients across the inner mitochon-drial membrane. However, the role of mPTP is to reversibly open to protect cells against stress. If mPTP remains stuck in the open position the cell dies. In contrast, ScMUC is probably dedicated to deplete oxygen from the medium in order to kill competing organisms. Such O2 depletion would be better achieved if oxidative phosphorylation is at least mildly uncoupled. Still, when oxida-tive phosphorylation is needed ScMUC should be able to close. To test this, the reversible opening and closing of ScMUC in the presence of different effectors was tested in isolated mitochondria from S. cerevisiae. Evaluations were conducted at different incubation times, monitoring the rate of O2 consumption, mitochondrial swelling and the transmembrane potential. It was observed that ScMUC did remain reversibly open for minutes. A low energy charge (ATP/ADP) closed the chan-nel. In addition, high Ca2+ promoted closing and it was a highly powerful effector.

scholarly journals In vitro and in vivo effect of 3-Para-fluorobenzoyl-propionic acid on rat liver mitochondrial permeability transition pore opening and lipid peroxidation

2020 ◽  
Vol 5 (1) ◽  
pp. 39-44 ◽  
Author(s):  
Adeola O. Olowofolahan ◽  
Omosola L. Bolarin ◽  
Olufunso O. Olorunsogo
Keyword(s):  
Lipid Peroxidation ◽  
Cytochrome C ◽  
Propionic Acid ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Mitochondrial Atpase ◽  
Cytochrome C Release ◽  
Mitochondrial Permeability ◽  
Pore Opening

AbstractThe opening of mitochondrial permeability transition (mPT) pore is a well recognized important event in the execution of mitochondrial-mediated apoptosis. Some bioactive compounds induce apoptosis in tumour cells via the induction of mPT pore opening. This study therefore investigated the effect of 3-Para-fluorobenzoyl-propionic acid (3PFBPA), a metabolite of haloperidol on mPT pore, mitochondrial ATPase activity (mATPase), mitochondrial lipid peroxidation (mLPO) and cytochrome c release (CCR). Thirty-two male Wistar rats, were acclimatized for 14 days in clean cages. After 30 days of treatment, they were sacrificed and the liver mitochondria isolated using differential centrifugation. The mPT pore, mATPase, mLPO and CCR were determined by standard methods using a spectrophotometer. The mPT pore opening was induced by 3PFBPA by 1.4, 3.6, 5.6, 6.6 and 7.4 folds, when compared with the control. Also, there was release of cytochrome c and enhancement of mATPase activity by 3PFBPA. The results also show that 3PFBPA reduced lipid peroxidation. However, oral administration of 3PFBPA at 50, 100 and 200 mg/kg did not have any effect on mPT pore opening and mATPase activity when compared with the control but there was inhibition of mLPO. These findings suggested the pharmacological potential of 3PFBPA against the pathological processes related to insufficient apoptosis (based on the in vitro data) and oxidative stress due to its anti-lipidperoxidative effect.

scholarly journals Metformin induces apoptosis via uterus mitochondrial permeability transition pore opening and protects against estradiol benzoate-induced uterine defect and associated pathophysiological disorder in female Wistar rats

2021 ◽  
Vol 45 (1) ◽  
Author(s):  
Adeola Oluwakemi Olowofolahan ◽  
Obinna Matthew Paulinus ◽  
Heritage Mojisola Dare ◽  
Olufunso Olabode Olorunsogo
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Estradiol Benzoate ◽  
Histological Evaluation ◽  
Mitochondrial Atpase ◽  
Rat Uterus ◽  
Mitochondrial Permeability ◽  
Pore Opening

Abstract Background Some antitumor or anticancer agents have been shown to execute cell death by induction of mitochondrial permeability transition (mPT) pore opening in order to elicit their chemotherapeutic effect. Therefore, this study investigated the effect of metformin on cell death via rat uterus mPT pore and estradiol benzoate-induced uterine defect and associated pathophysiological disorder in female rat. Mitochondria were isolated using differential centrifugation. The mPT pore opening, cytochrome c release and mitochondrial ATPase activity were determined spectrophotometrically. Caspases 9 and 3 activities, MDA and estradiol levels and SOD, GSH activities, were determined using ELISA technique. Histological and histochemical assessments of the uterine section were carried out using standard methods. Results Metformin at concentrations 10–90 μg/mL, showed no significant effect on mPT pore opening, mATPase activity and release of cytochrome c. However, oral administration of metformin caused mPT pore opening, enhancement of mATPase activity and activation of caspases 9 and 3 significantly at 300 and 400 mg/kg. Metformin protected against estradiol benzoate (EB)-induced uterine defect and other associated pathophysiological disorder. It also improved the antioxidant defense system. The histological evaluation revealed the protective effect of metformin on the cellular architecture of the uterus while the histochemical examination showed severe hyperplasia in the uterine section of EB-treated rats, remarkably reversed by metformin co-treatment. Conclusion This study suggests that metformin at high doses induces apoptosis via rat uterus mPT pore opening and protects against EB-induced uterine defect (hyperplasia) and associated pathophysiological disorder.

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